The extracellular matrix (ECM) is a principal component of many tumor types including, most notably pancreatic ductal adenocarcinoma (PDAC). The ECM in PDAC is rich in fibrillar collagens, which provide structural support and promote tumor cell survival and chemoresistance. Collagen expression and deposition is a complex process that is orchestrated in part by the matricellular protein SPARC. Many activities have been ascribed to SPARC although a unifying hypothesis of SPARC function is lacking. We propose that SPARC has evolved to control collagen binding to the cell surface and therefore is well-placed to reduce collagen-facilitated growth factor signaling. Amongst the widely distributed collagen receptors are integrins and two homologous receptor tyrosine kinases, the discoidin domain receptors, DDR1 and DDR2. DDRs have been implicated in regulating cell proliferation, adhesion, migration, ECM remodeling, and response to growth factors, including transforming growth factor (TGF). TGF is a prominent cytokine in the PDAC microenvironment that has been implicated as both a suppressor and promoter of tumor progression. Importantly, collagen signaling can facilitate the tumor promoting effects of TGF. We are interested in exploring if SPARC participates in DDR signaling and if this impacts TGF-mediated effects in PDAC. We propose that SPARC functions to limit collagen binding to DDRs. In support of this the binding sites on collagen for DDRs and SPARC have been shown to overlap. Furthermore, SPARC expression by pancreatic tumor cells decreases due to epigenetic regulation as the tumor progresses, a process that might facilitate DDR-mediated tumor invasion and metastasis. We hypothesize that SPARC functions to reduce DDR1/2 activation and that absence of SPARC enhances DDR-mediated PDAC progression. We will address this hypothesis by demonstrating that SPARC inhibits collagen I - DDR interaction and signaling. Further we will explore the biological consequences of DDR activity in vitro and in vivo. This proposal will address the function of SPARC in PDAC and explore strategies to inhibit collagen receptor activity. The function of the abundant ECM in PDAC is not understood. This project will create a new paradigm focused on the collagen-rich ECM as an active participant in disease progression and will also determine whether inhibition of collagen receptor activity blunts tumor cell invasion and chemoresistance. These studies have implications for our understanding of pancreatic tumor biology and may provide a much needed novel therapeutic strategy to enhance existing treatment strategies. PUBLIC HEALTH RELEVANCE: The underlying goal of this application is to further elucidate the function of collagen signaling in PDAC and demonstrate that SPARC is an endogenous inhibitor of DDR1/2 activity. We will demonstrate that a principal function of SPARC in the PDAC microenvironment is to reduce collagen-mediated signaling through DDRs. We further propose that collagen-induced activation of DDRs facilitates PDAC invasion and metastasis and our studies will provide a rationale for targeting DDR1/2 signaling as a therapeutic strategy for improving survival of patients diagnosed with PDAC.